This laboratory proposes to continue its studies into the molecular basis and treatment of retinoblastoma and uveal melanoma utilizing new molecular genetic techniques, immunohistochemical staining, and classic morphologic techniques. Specifically, we plan the following studies: 1. We wish to identify each of the genetic lesions involved in the initiation and progression of retinoblastoma. We first will determine what the cellular genes responsible for retinoblastoma developing in transgenic mice carrying the human papillomaviral (HPV) transgene E6 and E7 are, and how these differ from the genetic alterations responsible for human retinoblastoma 2. We will assess the role of N-myc in retinoblastoma transgenic mice by producing and characterizing IRBP-N-myc transgenic mice and opsin-N- myc mice 3. We will continue our study of 1,25 dihydroxy-16ene-23yneD3(16,23- vitaminD3) in transgenic mouse models and athymic nude mouse models to evaluate its efficacy in treatment of human retinoblastoma, hopefully in preparation of a human clinical trial. 4. We will evaluate the effectiveness of recombinant Herpes simplex virus (HSV) attenuated for neurovirulence in transgenic retinoblastoma mice. We will determine the effect of the mutants on the normal retina and on tumor parameters in transgenic retinoblastoma mice. 5. We will characterize pigmented tumors developing in the eyes of mice expressing SV40-T antigen (SV40-Tag) under the control of the mouse tyrosinase gene, and establish the relevance of these mice as a model for human uveal melanoma.